From a clinical point of view, it is clear that it would be helpful to use a biochemical test to better understand and differentiate the various states of growth hormone (GH) deficiency. The availability of such a test would permit the identification of the defect leading to the GH insufficiency and its degree; as well as to better decide when a GH treatment is needed and when it must be started. All conventional dynamic tests (i.e. clonidine, levodopa, arginine, insulin hypoglycemia) (Gil-Ad, Lancet 2:278, 1979; Plotnik, J. Clin. Endocrinol. Metab., 48:811, 1979; Frasier, Pediatrics, 53:929, 1974; Underwood, "Normal and Aberrant Growth," Williams Textbook of Endocrinology (eds. Wilson and Foster) p. 155, 1985, Saunders, Philadelphia) are unable to differentiate between GH-deficiency due to pituitary defect and that due to hypothalamic dysfunction involving the mechanisms engaged in GH neuroregulation. Moreover, these tests do not distinguish between hypothalamic defects leading to transiently or chronically impaired GH secretion; or particularly between Constitutional Growth Delay and Familial Short Stature, especially when, as is frequently observed, the former condition coexists with the genetic cause.
It was expected that the availability of growth hormone-releasing hormone (GHRH) would improve the ability to define GH-deficient states; however, the majority of growth hormone deficient subjects have a hypothalamic dysfunction and the majority of subjects tested have GH secretion in response to GHRH regardless of the etiology of their GH deficiency (Chatelain, Pediatric Research, 19:610, 1985). Otherwise, non-responder subjects could have been tested in a refractory hypothalamic somatotroph rhythm (HSR) phase (Devesa, Clinical Endocrinology (Oxf), 30:367, 1989), occurring either physiologically, during a normal trough period, or pathologically, as a consequence of a chronically increased somatostatinergic tone. Therefore, the use of GHRH alone has now been discarded for that purpose.
It is known that administering an agent to a normal subject that interferes with the hypothalamic release of somatostatin will enhance growth hormone release. This effect has been shown for clonidine, an alpha-2-adrenergic agonist, and pyridostigmine, a cholinergic agonist, although the mechanism of action is different for each drug (Ghigo, J. Endocrinol. Invest., 12:99, 1989). Likewise, galanin has been shown to potentlate GHRH-induced GH secretion in normal subjects (Davis, J. Clin. Endocrinol. Metab., 65:1248, 1987) via the cholinergic pathways (Chatterjee, J. Endocrinol., 116:R1-R2, 1988). It has also been recently postulated that the pyridostigmine plus GHRH test would allow the differentiation of GH deficiency due to pituitary secretory inability from that due to a hypothalamic defect, without distinguishing between the different states of GH neurosecretory dysfunctions (i.e., Congenital Delay of Growth, GH Neurosecretory Dysfunction) and Familial Short Stature (Ghigo, "Effects of the Enhancement of the Cholinergic Activity on Growth Hormone Secretion in Children: Clinical Implications," Recent Advances in Basic and Clinical Neuroendocrinology (eds. Casanueva and Dieguez), pp. 241-250, 1989, Excerpta Medica, Amsterdam). However, the fact that alpha-2-adrenoceptor blockade blunted the enhanced GH response to pyridostigmine plus GHRH (Devesa, [Devesa Mugica, the inventor herein] Abstracts Book, XII Panamerican Congress of Endocrinology, held November 2-8, 1990, Recife, Brazil) indicates that false negative responses (i.e. false pituitary defects) may also occur when utilizing this test. Moreover, pyridostigmine does not represent a useful treatment of short stature (Ghigo, "Effects of the Enhancement of the Cholinergic Activity on Growth Hormone Secretion in Children: Clinical Implications," Recent Advances in Basic and Clinical Neuroendocrinlogy (eds. Casanueva and Dieguez), pp. 241-250, 1989, Excerpta Medica, Amsterdam). While it has been shown that pretreatment with clonidine enhances the GH response to GHRH in short, normal children and adults (Reiter, J. Pediatr. Endocrinol., 3:21, 1988; Devesa [Devesa Mugica, the inventor herein] et al. J. Clin. Endocrinol. Metab., 71:1581-1588, 1990, it was not known whether such treatment could be extended to the differential diagnosis and treatment of the various states of GH-insufficiency in children.